Evaluation of hypotalamic neuronal impairment in vasopressin secretion during sepsis

Abstract

Sepsis and its complications (severe sepsis and septic shock) are still the main cause of death in intensive care units worldwide. Clinical and experimental studies, including those from our laboratory, have shown that in the early phase of sepsis there is a high plasma concentration of arginine vasopressin (AVP). However, during the pathophysiological process, although there is persistent hypotension, which would be a strong stimulus for the hormone secretion, its plasma concentrations remain inadequately low. One hypothesis suggested for this relative deficiency of AVP is the excessive production of nitric oxide (NO) in the central nervous system, which act by inhibiting hormone secretion, and could cause neuronal apoptosis by oxidative stress. In fact, our working group observed during experimental sepsis increased interleukin-1² (IL-1²) in plasma and the expression of inducible nitric oxide synthase (iNOS) in AVP-producing hypothalamic nuclei, which would explain the production center NO (observed by increased nitrate in the cerebrospinal fluid) and desregulate mitochondrial bioenergetics, causing oxidative stress and activation of the intrinsic pathway of apoptosis. In some infectious situations magnocellular neurons exhibit great vulnerability associated with increased expression of major histocompatibility complex class I (MHC-I) and infiltration of cytotoxic T lymphocytes or CD8 + (LT-CD8 +). Considering the role of AVP in the vasopressor response, the elucidation of the mechanisms of hormone synthesis could contribute to the therapy during sepsis. Thus, given the inflammatory conditions present in sepsis, our hypothesis is that the relative deficiency of AVP in the late phase of this pathophysiology is due to the increased expression of MHC-I and activation pathways of programmed cell death dependent on LT-CD8 + in magnocellular cells of the hypothalamus.